The present invention relates to a novel sustained-release pharmaceutical formulation of ketoprofen for daily oral administration, in the form of microgranules.
It also extends to the method for the preparation thereof and to the pharmaceutical compositions containing them.
Ketoprofen, or 2-(3-benzoylphenyl)propionic acid has been known since 1972 as a nonsteroidal anti-inflammatory medicinal product. It is commonly used for its analgesic, antipyretic and anti-inflammatory properties.
Ketoprofen is generally administered for the long-term symptomatic treatment of chronic inflammatory rheumatic diseases and of certain forms of osteoarthritis, and also for the short-term symptomatic treatment of acute triggering of abarticular rheumatism, microcrystalline arthritis, osteoarthritis, lumbago and severe radiculalgia.
The usual dose varies from 50 to 300 mg, preferably 100 to 200 mg, per day, in one or more doses.
Given that ketoprofen is commonly used in long-term treatments, and that its half-life is short (approximately 2 hours), sustained-release forms need to be used.
Document EP-A-403 383 describes sustained-release granules which each comprise a core comprising ketoprofen and microcrystalline cellulose and a coating comprising a water-soluble cellulose derivative and a water-insoluble cellulose derivative. The mass proportion of ketoprofen is between 60 and 80%; it is preferably equal to 75%. The granule cores are obtained by extrusion/spheronization and the coating thereof is carried out in a fluidized air bed using a solution of the two cellulose derivatives in a MeOH/CH2Cl2 mixture.
The granules described in EP-A-403 383, for example the specialty product Profenid(copyright) LP 200 mg, have the disadvantage of being obtained using a method which uses organic solvents.
Document EP-A-361 910 describes one of the dispersible granules prepared by adsorbing a pulverulent active principle having a granule size of less than 100 microns, on to a pulverulent excipient having a granule size of between 250 and 500 microns. The active principle may be ketoprofen and the excipient may be lactose. The particles obtained are mixed with an excipient which is solid at room temperature and which has a low melting point, for example stearic acid or a polyethylene glycol derivative. The mixture is heated until this excipient melts, and cooled in order to resolidify this same excipient once it has become attached to the particles of active principle.
The granules described in EP-A-361 910 contain active principle contents of the order of 25%, and appear to be restricted to these low contents.
Document EP-A-204 596 describes sustained-release ketoprofen granules obtained by extrusion of a mixture of ketoprofen, of one or more erodible polymers and of at least two lipid excipients, one of which has the property of gelling the polymer(s) and the other has lubricating properties. The polymer is, for example,. ethylcellulose, an acrylate or a vinylpyrrolidone/vinyl acetate copolymer. The lipid excipients are fatty acids or plant oils.
The granules described in EP-A-204 596 unadvantageously have release profiles which are extremely variable from one formulation to the other.
Document EP-A-667 148 describes delayed-release ketoprofen tablets consisting of a core of active principle coated with a cationic polymer and then with an anionic polymer. The cationic polymer is soluble at a pH of less than or equal to 6, for example an aminoalkyl methacrylate copolymer. The anionic polymer is soluble at a pH of greater than or equal to 5.5. The anionic polymer may be chosen from a methacrylic acid/methacrylate L copolymer (Eudragit L(copyright)), a methacrylic acid/methacrylate S copolymer (Eudragit S(copyright)) and hydroxypropylmethylcellulose.
The study of the bioavailability of this formulation (FIG. 2 of document EP-A-667 148) shows that the plasma concentration of ketoprofen is virtually zero for the 13 hours following administration of the tablet containing 50 mg of ketoprofen, and then increases in linear fashion up to 1.5 xcexcg/ml during the next 3 hours.
The specialty product ORUVAIL(copyright) 200 mg is manufactured using granules consisting of sucrose and starch, encoated with shellac and ethylcellulose. However, products containing shellac pose problems of stability. In addition, the preparation of a formulation containing shellac and ethylcellulose requires the use of an organic solvent.
The object of the present invention is to provide an oral sustained-release formulation of ketoprofen which lacks the drawbacks of the prior art, i.e.
the preparation of which uses no organic solvent, and
the excipients of which are chemically compatible so as to confer on the formulation good stability over time.
For this reason, the present invention relates to sustained-release ketoprofen microgranules, each consisting of an active core containing ketoprofen coated with a polymeric layer which allows sustained release of the active principle, characterized in that the polymeric layer contains Eudragit(copyright) RL and Eudragit(copyright) RS in a mass proportion of between 80/20 and 95/5, preferably approximately equal to 90/10.
Eudragit(copyright) RL and Eudragit(copyright) RS are aqueous dispersions at 30% of the copolymer poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) in the proportions 1/2/0.2 and 1/2/0.1, respectively.
The combination of Eudragit(copyright) RL and Eudragit(copyright) RS according to the invention has many advantages.
Eudragit(copyright) RL and Eudragit(copyright) RS are water-miscible in any proportion and do not require the use of organic solvents.
The film obtained using Eudragit(copyright) RL and Eudragit(copyright) RS is insoluble in water and in digestive fluids, to such an extent that the active principle is released by diffusion; in addition, the permeability of this film is independent of the pH, such that the release of the active principle is independent of the local and individual variations of the digestive tract.
The properties of the film containing Eudragit(copyright) RL and Eudragit(copyright) RS are perfectly suitable for coating granules.
The total mass of Eudragit(copyright) RL and Eudragit(copyright) RS contained in the polymeric layer represents between 1 and 8% of the mass of the microgranule, preferably 2 and 5%.
Advantageously, the polymeric layer coating the core contains a plasticizer, such as triethyl citrate, and/or a lubricant, chosen from pharmaceutically acceptable lubricants, such as colloidal anhydrous silica or Syloid(copyright).
The plasticizer enhances the elasticity of the polymeric film and decreases the temperature at which the film forms. The plasticizer represents 10 to 20% by weight of the dry mass of Eudragit(copyright) RL and RS.
The lubricant represents 10 to 30% by weight of the dry mass of Eudragit(copyright) RL and RS.
The mass of ketoprofen contained in the active core represents 50 to 80% of the mass of the microgranule, preferably 65 to 75%, more preferably 70% approximately.
The active core advantageously consists of a neutral support grain coated with ketoprofen and with a binding agent, chosen from pharmaceutically acceptable binding agents, for example a polyacrylate. In this embodiment, the neutral support grain represents 10 to 40% by weight of the mass of the microgranule, preferably 20 to 25%.
The active core of the microgranules of the invention preferably contains Eudragit(copyright) NE 30 D as a binding agent.
Eudragit(copyright) NE is an aqueous dispersion at 30% of an acrylic copolymer: poly(ethyl acrylate, methyl meth-acrylate) in the proportions 2/1.
Eudragit(copyright) NE has the advantage of being chemically compatible with the Eudragit(copyright) RL and RS contained in the enteric layer. It forms a film which is insoluble in water and in the digestive fluids.
A subject of the present invention is also a method for preparing the sustained-release ketoprofen microgranules presented above.
The method according to the invention is characterized in that it comprises a step for coating the active core by spraying an aqueous suspension containing Eudragit(copyright) RS and Eudragit(copyright) RL.
The active core is advantageously obtained by assembling the ketoprofen on neutral support grains with an aqueous suspension of a binding agent such as a polyacrylate.
According to a preferred embodiment, a first step of the method consists in preparing an xe2x80x9cassemblyxe2x80x9d suspension consisting of a 30% by weight aqueous suspension of Eudragit(copyright) NE 30D(copyright).
The assembly of the ketoprofen is carried out in a sugar-coating pan on neutral support grains, by discontinuous spraying of the suspension described above, alternating with sequences of dusting of the ketoprofen.
The microgranules are then sieved and dried at approximately 60xc2x0 C. for at least 10 hours.
A second step consists in preparing a coating suspension consisting of a 50% by weight aqueous solution of a mixture of Eudragit RL(copyright), Eudragit RS(copyright), silica and triethyl citrate in mass proportions of between 8/2/2/2 and 9.5/0.5/2/2, preferably equal to 9/1/2/2.
The microgranules to be coated are then placed in a sugar-coating pan and sprayed continuously with the coating suspension described above.
The coated microgranules are then sieved and dried at approximately 40xc2x0 C. for 4 to 8 hours.
The coating may be carried out in several steps, depending on the desired kinetics.
The dried microgranules may optionally be lubricated with talc, and then placed in gelatin capsules or tablets, containing 50 to 300 mg, preferably 100 mg to 200 mg, of ketoprofen.
The present invention also relates to any pharmaceutical composition which contains the microgranules which are described above and which can be obtained using the method which has just been presented, the mass of the microgranules contained in said composition corresponding to a daily dose of 50 to 300 mg, preferably 100 to 200 mg, approximately, of ketoprofen.
The in vivo dissolution profile of the microgranules and of the gelatin capsules according to the invention is such that
15 to 35% of the active principle, preferably 20 to 30%, has been released after two hours,
45 to 70% of the active principle, preferably 50 to 65%, has been released after 6 hours,
more than 65% of the active principle, preferably 70%, or even 80%, has been released after 12 hours.